Pseudohypoxia again, how to turn off the correct response to lack of oxygen?
I will try to follow up on several previous posts, because, as you may have already understood, inducing pseudohypoxia under conditions of relative sufficient oxygen fundamentally affects the metabolism of the cell and thus the entire organism. The main control element, the shift lever, is the presence of the transcription factor HIF-1α, which, through the control of HIF-1, turns hundreds of genes on and off to adjust the metabolism according to the current conditions.
We have also already recognized that it is not our enemy, but a helping hand. It appears whenever the cell has some problems. It typically occurs when there is a lack of oxygen, but not only that. It also occurs when there is an excess of fuel, i.e. an excess of glucose, fats, pyruvate, Acetyl-CoA and NADH molecules, when it functions as a safety valve and releases excess fuel in the form of lactate using the MCT4 back door.
Here we have shown that one of the control elements is superoxide O2-, which controls the rate of entry of citrate into the next stages of the TCA cycle. Superoxide and hydrogen peroxide H2O2, which is formed from superoxide, increases the level of citrate, which further controls the entry of fuel into the cell. If problems arise with fuel oxidation, hydrogen peroxide levels increase and HIF-1α is activated. The cell switches to fermenting glucose to lactate and saves itself. The mechanism by which this takes place is not entirely clear. It is quite possible that stopping the TCA cycle raises the level of succinic acid (succinate), which can stop the hydroxylation of HIF-1α and thus stabilize it. Hydrogen peroxide is closely linked to the oxidation of fuel NADH/FADH2 and creates the signal "we have a fully charged battery", i.e. the inner mitochondrial membrane. This is the signal to slow down the TCA cycle right at its start, the citrate level will increase and this will normally slow down both glucose and fat entry.
Using the example of a heart attack, we learned that if excess fats wander in the bloodstream in the form of free / non-esterified fatty acids, bound to albumin, or worse to calcium, they increase the rate of hydrogen peroxide breakdown by their presence. Depending on which fatty acids they are, they can increase or decrease the level of hydrogen peroxide and therefore can influence the response to oxygen deficiency. But they also affect the entire TCA cycle, enabling detours in it. Normally, the entire cycle runs inside the mitochondrion in the so-called matrix. However, if there is enough NADP+, it is possible to carry out part of the cycle outside the mitochondria, i.e. in the cell cytosol. It is probably no coincidence that this pathway bypasses regulation by hydrogen peroxide. The cycle is then controlled probably by malate, which is one of the many intermediates of the TCA cycle. Fat oxidation always produces a small amount of superoxide, even when the battery (inner mitochondrial membrane) is discharged. This will also ensure a steady supply of NADP+ for the bypass. Beta oxidation of fats supplies the TCA cycle with Acetyl-CoA fuel, this activates pyruvate carboxylase and oxaloacetate production and can also increase enzyme acetylation and hence deactivation. But this can raise the level of malate, which then regulates the speed of the TCA cycle instead of superoxide and hydrogen peroxide. Succinate levels may even rise enough to trigger mild pseudohypoxia. It looks harmless, but if there is a problem with the oxidation of the fuel in this situation (eg a heart attack), the cell will not react at all. But the researchers found that it responded to increased succinate. How? I think the mechanism is that succinate first temporarily triggers severe pseudohypoxia, drains excess fuel as lactate, this lowers malate levels, which allows the TCA cycle to run. Additionally it restores NAD+ levels, activates deacetylation by SIRT enzymes, and allows to pass the control of the TCA cycle to superoxide and hydrogen peroxide. Thus, it is possible to restore the correct response to hypoxia and subsequently restore the correct function of the cell in normoxia, e.g. after a heart attack.
Altogether, this will allow us to explain why the forced shutdown of MCT4 lactate transporters, as described in the previous post, causes changes in the levels of TCA cycle intermediates. The level of malate stops the enzyme succinate dehydrogenase, so the production of fumarate decreases and the level of succinate increases, see the picture above the paragraph. The numbers indicate the coefficient of variation upon closure of the MCT4 transporters. You can see that malate, succinate and citrate have increased. Citrate stops the fuel supply, succinate increases pseudohypoxia or hypoxia, and malate stops the TCA cycle. So the cell tries to save the day and open the MCT4 transporter more and promote fermentation. But the researchers intentionally blocked MCT4, which eventually led to increased glutamate production.
So we can speculate that there are at least two ways to pseudohypoxia, high H2O2 means excess fuel, or some problems with the electron transport chain (oxidation), specifically it can be the result of excess fuel Acetyl-CoA (acetylation) or lack of reduced glutathione. The result is the stimulation of HIF-1 and the reduction of beta oxidation of fats and the transition to the building (anabolic) mode, the formation of fats, membranes, blood vessels, and new cells. Or there is not enough peroxide H2O2 for proper regulation of the TCA cycle, then malate takes it over, followed by HIF-1 in pseudohypoxia, but reaction to real hypoxia is suppressed. This can happen when glutathione peroxidase and glutathione reductase are too active. The latter, by the way, produces NADP+, thus supporting the detour of the TCA cycle through the cytosol, which disables regulation by peroxide H2O2. This mechanism, as you may have guessed, is caused by an excess of omega-6 linoleic acid in the diet and in adipose tissue.
So what is the solution that could lead to overcoming pseudohypoxia? Above all, it is clear that in both cases it is caused by an excess of fuel. The cell's regulatory mechanisms try to compensate for this, but not enough. An excess of fuel in the blood is the result of stress, so calmness and elimination of stress is a necessary basis. But if the excess fuel is due to omega-6 linoleic acid, then even that is not enough. Succinate helped the researchers in this study. Even Brad Marshall mentions it on his blog. I would rather solve it by adding MCT oil, which increases the activity of the second mitochondrial complex, i.e. succinate dehydrogenase, and restores regulation with H2O2. And for that, of course, it is good to exclude linoleic acid from the diet, inhaling highly diluted hydrogen peroxide or applying ozonated olive oil to the skin could also help. But I can't advise anyone, this information is for study and may not be true at all. Search and don't believe, search for yourself and check everything.
References:
Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase
Fatty Acids Prevent Hypoxia-Inducible Factor-1a Signaling Through Decreased Succinate in Diabetes
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